Understanding the molecular mechanisms used by human immunodeficiency virus type 1 (HIV-1) to kill CD4+ T lymphocytes should contribute to finding new therapies capable of interrupting the progression to acquired immunodeficiency syndrome (AIDS). Studies with peripheral blood T cells infected with primary clinical isolates of HIV-1 have shown that HIV-1 kills T cells by trapping the cells at a late point in the cell cycle (G2/M interface). These activated but arrested proliferating cells die when they are unable to complete the cell cycle and an abnormal form of programmed cell death is initiated. The characteristics of this programmed cell death, which include accumulation of proteins found only in cells about to enter mitosis, define the killing event as a pre- mitotic catastrophe. These studies are now being performed on T cells and lymph nodes from HIV-infected individuals 1) to identify populations of T cells in infected individuals undergoing this killing process and 2) to correlate the percentage of affected cells with disease progression to AIDS. We further demonstrated with a panel of metabolic inhibitors that HIV-mediated programmed cell death differed substantially from the programmed death of CD4+ T cells which occurs during normal T cell development (negative selection). These observations have thereby increased the likelihood that clinically useful agents can be developed to selectively inhibit the HIV-killing process without initiating unacceptable toxicity in normal T cells.